Serotonin is a neurotransmitter involved in multiple brain functions. The receptors of serotonin commonly known as 5-hydroxy tryptamine (5-HT) receptors are extensively expressed in various sites in the body such as brain, blood vessels, heart valves, gastrointestinal tract, platelets, etc. Binding of serotonin to 5-HT receptors can induce both excitatory and inhibitory neurotransmission. There are fourteen 5-HT receptors identified. Serotonin is capable of exerting complex cardiovascular effects, including hypotension or hypertension, vasodilation or vasoconstriction, bradycardia or tachycardia etc. The action exerted by serotonin depends on the nature of the 5-HT receptor it binds along with the receptor density and sensitivity. Serotonin receptors 5-HT1A, 5-HT1B and 5-HT1D are expressed in blood vessels and central nervous system. Binding of serotonin to these receptors causes vasoconstriction in blood vessels. Drugs binding to 5-HT1B and 5-HT1D receptors are used in treatment of Migraine. However, since 5-HT1B receptors are also expressed in heart valves, long term administration of these drugs can cause cardiovalvular diseases. Similarly apart from vasoconstriction, 5-HT1A receptors are also involved in nonciceptive signal transduction. Agonist of 5-HT1A receptor can reduce pain perception to a significant level of almost 80% as compared to standard opioid drugs. Hence it is apparent that the downstream effect of serotonin varies depending on the type of 5-HT receptor it binds.
The international classification of headache disorders (2nd edition) describes Migraine as a neurovascular disorder characterized by severe and throbbing unilateral headache associated with anorexia, nausea, vomiting, photophobia and/or phonophobia. The most common types of Migraine are (i) Migraine with aura starting with visceral, sensory or motor symptoms followed by headache; and (ii) Migraine without aura—the headache is similar to (i) but not preceeded by aura.
Many theories exist to describe the etiology of migraine. The vascular theory states that migraine headaches result from dilatation of blood vessles which is caused by release of vasodilatatory substances like neuropeptides, neurokinins etc. It is generally accepted that this neurovascular syndrome is mainly caused by activation of trigeminovascular system. Certain brain structures that are possibly involved in Migraine have been identified as follows: the meningeal artery surrounded by mast cells in the meninges; large cerebral arteries; trigeminal nerve from meningeal arteries and cerebral arteries; and trigeminal nerve connecting the trigeminal ganglia to the trigemineal nucleus caudalis (TNC). TNC conveys the nociceptive signals to higher pain centers in the thalamus and cortex. Activation of trigemineal nerves can also cause the release of various neuropeptides including calcitonin gene related peptide at the sensory nerve endings. This causes vascular pathophysiology leading to neuro inflammation.
The serotonin theory is actually a broad statement that supports the role of increase in serotonin and 5-HIAA during the migraine attack. It has been reported that Migraine patients display an increased synthesis of serotonin in the brain as compared to normal subjects. This may lead to cortical hyperexcitability. Interestingly, it is also reported that Migraine is a low serotonin syndrome. Therefore, the involvement of serotonin in Migraine is not conclusive. Other hypotheses support the role that hormones and changes in anatomy play a role in migraine development. Hence the pathophysiology of Migraine is very complex and is not understood very clearly.
Selective serotonin reuptake inhibitors (SSRIs) are a class of compounds typically used in the treatment of depression and anxiety disorders. They increase the extracellular concentration of the neurotransmitter serotonin by inhibiting its reuptake into presynaptic neurons and increasing the serotonin available in the synaptic cleft to bind to the postsynaptic receptor. There is a misconceived notion that all SSRIs are useful drugs for Migraine. This is not true as increased levels of serotonin can bind to all 14 5-HT receptors with equal affinity and many of these are contraindicated for Migraine. Moreover, there are uncertainties about the expression of many of the 5-HT receptor proteins which are linked to other CNS conditions. For example, it is reported that 5-HT1A receptors are not synthesized in the CNS in case of high neurosteroid levels.
Lampl et al. (2010), in his article on Antidepressants for Migraine Prophylaxis published in European Neurological Journal has critically analyzed published data on efficacy of SSRIs for Migraine and concluded that the beneficial effects of SSRIs were equivalent to that seen in the placebo group following chronic therapy. This shows that SSRIs in general need not be useful for Migraine. Understanding the selectivity of a molecule to 5-HT receptor subtypes is crucial for determining its involvement in Migraine treatment.
Based on the definition of Migraine and its known pathophysiology, it is apparent that an ideal anti-Migraine drug should inhibit vasodilation (or cause vasoconstriction) and reduce pain perception or nociception. These two direct actions of a drug will offer potential relief from Migraine related symptoms. 5-HT1A receptors emerge as an ideal target for achieving these dual actions. Selective 5-HT1A receptor agonists have potential in offering a better anti-Migraine therapy than current standard of care for Migraine namely triptan class of drugs.
Neuropathic pain is yet another pathological pain condition characterized by persistent neuralgic pain independent of sensory stimulation along with hypersensitivity at the site of pain. It is associated with many diseases like diabetes, alcoholism, vasculitis, idiopathic polyneuropathy, spinal cord injury, cancer, stroke, HIV, degenerative neurological diseases, Guillain Barré syndrome, postherpetic neuralgia and trigeminal neuralgia. Neuropathic pain is caused by lesion or dysfunction of the peripheral or central nervous system which gives raise to symptoms of loss of sensation, paraesthesia and pain.
Neuropathic pain is not a unitary syndrome. It is a manifestation of a variety of underlying mechanisms including ectopic impulses of neuroma, changes of sodium and calcium channels in injured nerves, sympathetic activation, and deficient central inhibitory pathway are some of the pathological mechanisms.
Currently, there is no treatment which can prevent the development of Neuropathic Pain. Patients suffering from neuropathic pain do not respond to non-steroidal anti-inflammatory drugs (NSAIDs). Antidepressants and anticonvulsants are the standard of care prescribed for pain relief. However these drugs have incomplete efficacy and severe side-effects. The mechanism of action of antidepressants in treatment of Neuropathic Pain is not entirely understood. Saarto et al. (2010), in his review on antidepressants for Neuropathic Pain published in The Cochrane Library showed that only about one-third of patients using antidepressants have relief from Neuropathic pain and about one-fifth of the patients discontinue treatment due to severe side-effects. Based on the existing evidence of published clinical trials, SSRI drugs are not effective in treatment of Neuropathic Pain while tricyclic antidepressants are more effective in providing clinically meaningful pain relief. The activity of 5-HT1A receptor agonists in reducing pain perception may have potential in treatment of neuropathic pain.
Meijer et al. (1994, Eur J Pharmacol., Vol. 266, No. 3, pp. 255-61), demonstrated that prolonged exposure of rat hippocampal cells to neurosteroids like corticosterone inhibited expression of 5-HT1A receptor mRNA. Under conditions of stress in humans, excess of neurosteroid secretion can down-regulate 5-HT1A receptor expression which in turn increases the pain sensitivity. This explains Myalgia or chronic pain experienced by patients suffering from depressive disorders. Prolonged exposure of body's tissues to high levels of cortisol neurosteroid results in a disorder known as Cushing's syndrome or hypercortisolism. Cushing's syndrome can be induced by long term exogenous administration of steroid hormones like glucocortocoids, adrenocorticotropic hormone (ACTH), contraceptive pills containing estrogen hormone and other endogenous abnormalities in the body. Symptoms of Cushing's syndrome includes one or more of the following: diabetes, high blood pressure, upper body obesity, increased fat deposition around the neck, rounded face, thinning of arms and legs, severe fatigue, weak muscles etc. Irritability, anxiety, cognitive disturbances and depression are common behavioural symptoms associated with Cushing's syndrome. Treatment of Cushing's syndrome includes administration of cortisol inhibiting drugs like ketoconazole and metyrapone along with drugs for symptomatic treatment.
The present disclosure is related to treatment and management of Cushing's syndrome, Migraine, Neuropathic pain, Myalgia and related pains. These are neurological disorders that require long term management therapy. The present disclosure aims at using a botanically derived composition comprising 15-50% asiaticoside and 20-50% madecassoside optionally along with excipients, as a safe and effective treatment option for chronic administration in patients suffering from these diseases.
Bhaskaran et al. (US20080194499) discloses a composition for serotonin reuptake inhibition comprising 15-50% asiaticoside and 20-50% madecassoside. This document shows that the composition is helpful in treatment of diseases which are mediated by reduction in serotonin levels namely depression, mood elevation, gastric emptying etc., by increasing the levels for serotonin neurotransmitter. This document teaches that the composition potentiates serotonin effects by blocking reuptake of serotonin. However, there is no suggestion or clarity in the application of this composition in addressing the effects of nociceptive and neuropathic pain perception, the attenuation of vasodilation and modulating hypersecretion of neurosteroids. This application also does not teach anything about the reduction of symptoms associated with Cushing's syndrome (hypercortisolemia). This application talks about increasing the concentration of serotonin by reducing reuptake in presynaptic receptors.